piperidines and 7-chlorokynurenic-acid

Intrathecal (i.t.) administration of D-cycloserine (100 and 300 fmol), a partial agonist of the glycine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, produced a behavioral response mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank in mice, which peaked at 5 - 10 min and almost disappeared at 15 min after the injection. The behavior induced by D-cycloserine (300 fmol) was dose-dependently inhibited by an intraperitoneal injection of morphine (0.5-2 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also dose-dependently inhibited by i.t. co-administration of 7-chlorokynurenic acid (0.25-4 nmol), a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex; D-(-)-2-amino-5-phosphonovaleric acid (62.5-500 pmol), a competitive NMDA receptor antagonist; MK-801 (62.5-500 pmol), an NMDA ion-channel blocker; ifenprodil (0.5-8 nmol); arcaine (31-125 pmol); and agmatine (0.1-10 pmol), all being antagonists of the polyamine recognition site on the NMDA receptor ion-channel complex. However, [D-Phe7,D-His9]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10,376, a tachykinin NK2-receptor antagonist, had no effect on D-cycloserine-induced nociceptive behavior. These results in the mouse spinal cord suggest that D-cycloserine-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the glycine recognition site and that it does not involve the tachykinin receptor mechanism.

Topics: 2-Amino-5-phosphonovalerate; Agmatine; Animals; Cycloserine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Injections, Spinal; Ion Channels; Kynurenic Acid; Mice; Morphine; Neurokinin A; Nociceptors; Pain; Peptide Fragments; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Tachykinin; Substance P

Responding of rats was maintained under a 120-response fixed ratio (FR) schedule of food delivery, and animals received individual and combined injections of N-methyl-D-aspartic acid (NMDA), phencyclidine hydrochloride, (+)-MK-801 hydrogen maleate (MK-801), (+/-)-2-amino-5-phosphonopentanoic acid (AP5), 7-chlorokynurenic acid (7CK), ifenprodil tartrate, N(G)-nitro-L-arginine methyl ester hydorchloride (L-NAME), 7-nitroindazole, aminoguanidine hemisulfate, L-arginine, molsidomine, sodium nitroprusside, and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8). Behavioral suppression after NMDA was completely and dose-dependently reversed by MK-801, phencyclidine, AP5, and aminoguanidine; partially and dose-dependently attenuated by molsidomine, ifenprodil, and 7CK; and not attenuated at all by L-NAME, 7-nitroindazole, or TMB-8. These findings suggested that behavioral suppression after NMDA was associated with nitric oxide from the inducible synthase. In a second series of experiments, comparable behavioral suppression by 0.1 mg/kg MK-801, but not 3 mg/kg phencyclidine, was attenuated by nitroprusside, molsidomine, and L-arginine, suggesting that suppressions from MK-801 and phencyclidine were mediated by different final common pathways, and that behavioral suppression from MK-801, but not phencyclidine, may be associated with Ca(2+)-dependent nitric oxide.

Topics: 2-Amino-5-phosphonovalerate; Animals; Arginine; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Gallic Acid; Guanidines; Indazoles; Injections, Intraperitoneal; Kynurenic Acid; Molsidomine; N-Methylaspartate; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroprusside; Phencyclidine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Intrathecal (i.t.) administration of big dynorphin (1-10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5-15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1-30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-2 mg/kg) and also dose-dependently, by i.t. co-administration of D(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe(7),D-His(9)]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics, Opioid; Animals; Behavior, Animal; Dizocilpine Maleate; Dynorphins; Endorphins; Enkephalins; Excitatory Amino Acid Antagonists; Injections, Spinal; Kynurenic Acid; Male; Mice; Morphine; Neurokinin A; Nociceptors; Peptide Fragments; Piperidines; Protein Precursors; Receptors, N-Methyl-D-Aspartate; Receptors, Tachykinin; Substance P

We investigated the role of the NMDA receptor complex in DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate)-induced seizures in mice. The seizure threshold of DMCM was evaluated using an i.v. infusion technique. Pretreatment with the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cycloheptan-5,10-imine maleate) or phencyclidine (PCP) significantly increased the seizure threshold for DMCM. Furthermore, the seizure threshold of DMCM was increased by intracerebroventricular (i.c.v.), but not intrathecal (i.t.), pretreatment with MK-801. Moreover, 7-chlorokynurenic acid, a glycine site antagonist, also increased the seizure threshold of DMCM, whereas ifenprodil, a non-competitive polyamine site antagonist, did not. These findings indicate that the ion-channel binding site and the glycine binding site on the NMDA receptor complex in the brain may be involved in the expression of seizures induced by DMCM.

Topics: Animals; Carbolines; Cerebral Ventricles; Convulsants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraventricular; Injections, Spinal; Kynurenic Acid; Male; Mice; Mice, Inbred Strains; Phencyclidine; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Spinal Cord

The effects of several NMDA receptor antagonists on pentylenetetrazole-induced diazepam-withdrawal seizure were examined in mice. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was inhibited by pretreatment with MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate), 7-chlorokynurenic acid and ifenprodil. Furthermore, MK-801 and ifenprodil, at doses which did not affect the threshold of pentylenetetrazole-induced seizure in control mice, also significantly suppressed the decrease in the seizure threshold during diazepam withdrawal, whereas 7-chlorokynurenic acid did not. These findings suggest that overactivity of an ion channel site and an ifenprodil binding site on the NMDA receptor may play an important role in the hypersensitivity of pentylenetetrazole-induced seizure in diazepam-withdrawn mice.

Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraperitoneal; Injections, Subcutaneous; Kynurenic Acid; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

NT2 cells are a clonal line of human teratocarcinoma cells that exhibit N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity after terminal differentiation into NT2-N neurons. In this study, we used modulation of glutamate excitotoxicity to characterize the pharmacological properties and specific antibodies to determine the individual subunits of NMDA receptors expressed by NT2-N neurons. The glycine site antagonist 7-chlorokynurenic acid completely blocked glutamate toxicity in a dose-dependent manner. Histamine and the polyamine agonists spermine and spermidine enhanced glutamate toxicity in a dose-dependent manner consistent with expression of an NR1-NR2B combination of subunits. The efficacy of polyamine agonists suggests the expression of one or more splice variants of the NR1 subunit that lack the putative surface loop encoded by exon 5. Surprisingly, the putative inverse agonists diaminodecane and diaminododecane also enhanced toxicity in a dose-dependent manner. The antagonists arcaine and ifenprodil completely blocked glutamate toxicity in NT2-N cells. The atypical antagonist ifenprodil inhibited toxicity with a uniformly high affinity characteristic of interaction with the NR1-NR2B combination of subunits. Expression of both NR1 and NR2 subunits were detected by Western blot analysis. Neither protein was detectable in undifferentiated cells. In contrast, 70-fold lower levels of the NR2A subunit were detected in both differentiated and undifferentiated cells. The pharmacological and immunological results indicate that a functional NR1-NR2B combination of subunits is expressed by NT2-N neurons. Despite the immunological detection of NR2A subunit, no functional combination of NR1 and NR2A subunits could be demonstrated.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Glutamic Acid; Humans; Immunoblotting; Kynurenic Acid; Neurons; Piperidines; Putrescine; Rats; Receptors, N-Methyl-D-Aspartate

1. The involvement of the N-methyl-D-aspartate (NMDA) receptor macrocomplex in the development of spermine-induced CNS excitation in vivo was investigated. 2. Injection of 100 micrograms of spermine into the left lateral cerebral ventricle of female Laca mice (20-25 g) resulted in the development of two distinct phases of CNS excitatory effects which were quantified by a scoring system. 3. The first phase effects occurred within minutes of injection and generally lasted for about 1 h. Most mice showed scratching of the upper body, frequent face washing and some mice developed clonic convulsions. By about 2 h after injection, the second phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generally within 8 h of injection. 4. Pretreatment of the mice with dizocilpine (0.3 mg kg-1, i.p.) resulted in antagonism of the first phase of spermine-induced effects, but a higher dose (0.3 mg kg-1, (x2), i.p.) was necessary to inhibit the second phase effects. 5. Whereas the glutamate antagonist, 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (D-CPP) (10, 20 mg kg-1, i.p.), the glycine antagonist 7-chlorokynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenprodil (30, 60 mg kg-1, i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffective against the development of the second phase of effects. 6. Co-administration of ifenprodil with either D-CPP or 7-chlorokynurenate resulted in a dose-dependent antagonism of the development of the second phase of spermine-induced effects. 7. It is concluded that the development of the two temporally distinct phases of spermine-induced effects may be mediated by pharmacologically distinct mechanisms, although the results suggest that the NMDA receptor macrocomplex may be involved in both phases of effects. Furthermore, a moderate dose of D-CPP or 7-chlorokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.

Topics: Animals; Brain; Cerebral Ventricles; Dizocilpine Maleate; Female; Kynurenic Acid; Mice; Neuroprotective Agents; Piperazines; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Spermine; Tremor

Antagonists at four distinct regulatory sites on the N-methyl-D-aspartate (NMDA) receptor were tested for their ability to attenuate NMDA-mediated chronic excitotoxicity and the consequences on AT8 tau immunoreactivity in neuronal cultures. Excitotoxicity was monitored in cultures by diacetate fluorescein staining. Immunoreactivity of tau phosphorylated at serine 202 was quantified by laser confocal microscopy. The NMDA-receptor antagonists MK801, AP7 and 7-chlorokynurenate significantly blocked NMDA-induced cell death and significantly reduced AT8 tau immunoreactivity. NMDA antagonism by the polyamine site antagonist, ifenprodil, did not completely reverse the increase in AT8 tau immunolabeling induced by NMDA and did not completely protect NMDA-sensitive neurons, suggesting an heterogeneity in the NMDA receptor population.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cell Survival; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Fetus; Fluorescent Antibody Technique; Kynurenic Acid; Microscopy, Confocal; Neurons; Piperidines; Pregnancy; Rats; Receptors, N-Methyl-D-Aspartate; tau Proteins

In midbrain dopamine neurons in vitro, N-methyl-D-aspartate (NMDA) evokes oscillation of membrane potential and burst firing which are dependent on a ouabain-sensitive sodium pump. In the present study, we investigated the ionic dependence and pharmacological modulation of NMDA-mediated currents which might be important in burst firing. By use of patch pipettes to record membrane currents in whole-cell voltage clamps, we found that NMDA (10 microM) evoked inward currents that were significantly reduced in a low extracellular concentration of Na+ (25 mM), but not when extracellular Ca+2 was decreased from 2.5 to 0.5 mM. The current-voltage relationship for subtracted NMDA currents showed a prominent region of negative slope conductance which was absent when the slice was perfused with solution containing zero Mg++. 7-Chlorokynurenic acid, an antagonist at the nonstrychnine-sensitive glycine binding site, produced a concentration-dependent reduction in amplitude of excitatory postsynaptic currents mediated by NMDA receptors (IC50 = 15 +/- 3 microM). NMDA-activated currents were blocked by phencyclidine (IC50 = 130 +/- 65 nM), dizocilpine maleate (MK-801) (1 microM) and ketamine (100 microM), but not by amantadine (1 mM). Spermine (100 microM), a polyamine which reportedly modulates NMDA currents in other neurons, presynaptically inhibited excitatory postsynaptic currents mediated by NMDA receptors but had no effect on the currents mediated by NMDA. We conclude that the most important factors for NMDA-induced burst firing are the relatively large Na+ influx through NMDA-gated channels and the strong voltage-dependent block of conductance by Mg++.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Agonists; In Vitro Techniques; Kynurenic Acid; Magnesium; Male; Membrane Potentials; N-Methylaspartate; Phencyclidine; Piperidines; Rats; Rats, Sprague-Dawley; Sodium; Spermine; Substantia Nigra; Ventral Tegmental Area

7-Chlorokynurenate, an antagonist at the glycine recognition site of the NMDA receptor complex, increases the binding of the competitive NMDA receptor antagonist [3H]CGP39653 ([3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) to well washed rat brain membranes but only in the presence of 100 microM spermine. Conversely, spermine only increases [3H]CGP39653 binding in the presence of 10 microM 7-chlorokynurenate, through a mechanism insensitive to the putative polyamine antagonists ifenprodil, arcaine or putrescine. Thus, the effects of glycine antagonists and polyamines on the binding of competitive NMDA receptor antagonists may depend on the residual glycine and polyamine content of the membrane preparation or the state of the glycine recognition site. These data further attest to the complexity of interactions between spermine and the glycine and glutamate recognition sites of the NMDA receptor.

Topics: 2-Amino-5-phosphonovalerate; Allosteric Regulation; Animals; Biguanides; Binding Sites; Glycine; In Vitro Techniques; Kynurenic Acid; Male; Piperidines; Prosencephalon; Putrescine; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spermine

Ifenprodil (30 mg/kg i.p.) when administered alone did not antagonise the stimulatory effects of intrastriatally administered N-methyl-D-aspartate (NMDA: 500 microM, via a dialysis fibre) on spermine or spermidine release. The effects of NMDA were antagonised by the intrastriatal co-infusion of the glycine site antagonist, 7-chlorokynurenate (100 microM). Lower concentrations of 7-chlorokynurenate (3 microM) were without effect on the NMDA response. In the presence of a subthreshold concentration of striatally infused 7-chlorokynurenate (3 microM), systemically administered ifenprodil (30 mg/kg i.p.) blocked the effects of NMDA on polyamine release and also potentiated the inhibitory effects of 30 microM 7-chlorokynurenate. These results demonstrate that synergism between glycine antagonists and polyamine antagonists, as previously observed in vitro, is also observed in vivo.

Topics: Animals; Chromatography, High Pressure Liquid; Drug Synergism; Glycine; Injections; Kynurenic Acid; Male; N-Methylaspartate; Neostriatum; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spermidine; Spermine

Antagonists of 4 distinct regulatory sites on the N-methyl-D-aspartate (NMDA) receptor were tested for their ability to attenuate NMDA-mediated acute excitotoxicity in isolated chick retina of various embryonic ages between days 11 and 19 in ovo. Acute excitotoxicity was monitored by histology and by release of endogenous gamma-aminobutyric acid (GABA) into the medium during 30 min of incubation with 50 microM NMDA. The uncompetitive PCP channel site antagonist, MK-801, the competitive antagonist, CGS 19755, and the strychnine-insensitive glycine site antagonist, 7-chlorokynurenate, completely blocked NMDA-induced cell swelling and increased GABA release at all ages tested. Potencies versus NMDA were MK-801 greater than CGS 19755 greater than 7-chlorokynurenate with IC50S of 0.02, 0.62, and 15 microM, respectively. NMDA antagonism by the polyamine site antagonist, ifenprodil, differed from other classes of antagonists in several respects. At the earlier embryonic ages tested (E12-13) ifenprodil provided differential protection; completely blocking somal and neuritic swelling in most but not all inner nuclear layer neurons and inner plexiform processes. In dose-response studies, ifenprodil attenuated the NMDA-induced increase in medium GABA at all ages tested with an Imax of 10 microM. Ifenprodil, however, showed a decreased ability to completely protect some NMDA-sensitive neurons. This was reflected both histologically and by GABA release. Maximal attenuation of NMDA evoked GABA release was 83, 80, 62 and 50% at days E12, 13, 15 and 19, respectively. Histologically, differential protection was seen at E12 and 13, in limited areas at E15, and was no longer present at E19.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Biogenic Polyamines; Chick Embryo; Dizocilpine Maleate; Kynurenic Acid; N-Methylaspartate; Pipecolic Acids; Piperidines; Receptors, Glutamate; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Retina

1. Agonists may act at any one of three sites on the N-methyl-D-aspartate (NMDA) receptor-effector complex to promote opening of the associated ion channel. The three sites are activated by i) NMDA, L-glutamate, aspartate, and other dicarboxylic amino acids; ii) glycine, D-serine, D-cycloserine, and others; iii) the polyamines spermine or spermidine, but not cadaverine or putrescine. 2. This opening by exogenous agonists is reflected by an enhanced binding of the phencyclidine-like dissociative anesthetic [3H]MK-801 to rat cortical membranes (well washed to remove endogenous agonists, e.g., L-glutamate, glycine). 3. The effects of adding combinations of agonists yielded stimulation approximately equal to the sum of each agonist's effect, suggesting that in the first approximation the three classes act at independent sites. 4. When the glutamate (E) site was antagonized with D-2-amino-5-phosphonopentanoate (D-AP5), no stimulation in binding could be elicited by agonists at the two other sites. Activation of the E site is therefore necessary but not sufficient for channel opening. 5. When the glycine (G) site was antagonized with 7-chlorokynurenate, no stimulation in binding could be elicited by agonists at the other two sites. Activation of the G site is therefore necessary but not sufficient for channel opening. 6. Of the two putative antagonists for the polyamine (PA) site, ifenprodil fails to completely inhibit the binding of [3H]MK-801, whereas arcaine inhibited [3H]MK-801 binding completely. We present data which question the selectivity of arcaine for the polyamine site, and propose that the polyamine site is merely modulatory, but neither necessary nor sufficient, for channel opening.

Topics: 2-Amino-5-phosphonovalerate; Adrenergic alpha-Antagonists; Animals; Biguanides; Binding, Competitive; Biogenic Polyamines; Biotransformation; Brain; Dizocilpine Maleate; Glutamates; Glutamic Acid; Glycine; In Vitro Techniques; Kynurenic Acid; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Spermidine; Spermine

The effects of spermidine on the binding of [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor complex was studied in human cerebral cortical membranes. [3H]MK-801 binding was increased from 56 +/- 5 fmol/mg protein (mean +/- S.E.M., n = 7) to 319 +/- 71 fmol/mg protein in the presence of 200 microM spermidine. The ED50 for spermidine stimulation of [3H]MK-801 binding was 89 +/- 22 microM (mean +/- S.E.M., n = 6). In the presence of glutamate (1 microM) plus glycine (1 microM) the ED50 was reduced to 5.5 +/- 0.7 microM. The increase in binding in the presence of spermidine was characterised by an increase in the rate of association of [3H]MK-801. In the presence of spermidine. [3H]MK-801 was inhibited by AP5. 7-chlorokynurenic acid and ifenprodil with IC50 values of 0.5 +/- 0.3 24 +/- 19 and 91 +/- 28 microM, respectively. None of these antagonists was a competitive inhibitor of the spermidine stimulation of [3H]MK-801 binding. Thus spermidine modulates the NMDA receptor complex in human brain, providing further evidence that the complex is similar in rat and human cortex.

Topics: Adrenergic alpha-Antagonists; Aged; Aged, 80 and over; Cerebral Cortex; Dizocilpine Maleate; Female; Humans; In Vitro Techniques; Kynurenic Acid; Male; Membranes; Piperidines; Radioligand Assay; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spermidine

The interaction between glycine and competitive N-methyl-D-aspartate (NMDA) antagonists was investigated. Glycine (IC50 = 170 nM) partially (approximately 60%) inhibited [3H]CGS-19755 ((+/-)-4-phosphonomethyl-2-piperdine carboxylic acid), but not [3H]CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) binding. The action of glycine was mimicked by D-serine and antagonized by 7-chlorokynurenate. CGS-19755 (IC50 = 230 nM) partially inhibited [3H]glycine binding from strychnine-insensitive sites; this effect was antagonized by NMDA. CPP and NPC 12626 (2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) inhibited [3H]glycine binding, but only at concentrations 100- to 1000-fold greater than required to displace [3H]CGS-19755 or [3H]CPP. These data provide the first evidence for bidirectional interactions between glycine and NMDA recognition sites and suggest pharmacological differences among competitive NMDA antagonists.

Topics: Amino Acids; Animals; Brain Chemistry; In Vitro Techniques; Kynurenic Acid; Male; Pipecolic Acids; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Serine